Novel Live Attenuated Cholera-Tetanus Bivalent Vaccine

Morehouse School Of Medicine, Atlanta GA

Investigators

Linked publications & trials

Abstract

Cholera continues to be a major public health problem in developing countries. During 2003 forty five[unreadable] countries officially reported to WHO 111,575 cases of cholera and 1,984 deaths. Unfortunately, there is still[unreadable] not an inexpensive and safe cholera vaccine affording long term protection in all age groups particularly in[unreadable] children under five years old. The live genetically attenuated cholera vaccine candidate Vibrio cholerae 638[unreadable] adhere strongly to mucosal surfaces in vitro and in vivo and induces strong local and systemic immune[unreadable] responses and protection against cholera in animal models and humans without inducing significant side[unreadable] effects (reactogenicity). Tetanus continues to be a global health problem that accounts for 14% of vaccinepreventable[unreadable] deaths and 500,000 cases of neonatal tetanus per year. Cholera and tetanus share similar[unreadable] geographic distribution. In this project we will develop a novel cholera-tetanus vaccine that lyses in the gut to[unreadable] deliver a tetanus protective antigen rather than being shed to the environment. To achieve this goal we will[unreadable] manipulate the bacterial quorum sensing system so that the live vaccine strain will only sense its cell density[unreadable] in vivo (low iron or anaerobiosis) to express a phage lysis gene under the control of a cell density-dependent[unreadable] promoter. Programmed cell lysis in the gut will allow the massive delivery of immunogenic and protective[unreadable] tetanus C fragment (TCP) to mucosal inductive sites. The capacity of this new vaccine to lyse in the small[unreadable] intestine, deliver TCP and induce protective immunity to cholera and tetanus will be determined using the[unreadable] suckling mouse model, adult rabbits ileal loops and the adult germ-free mice model. The development of the[unreadable] above cholera-tetanus combination vaccine could significantly improve the cost-benefit ratio of a massive[unreadable] vaccination program in endemic areas. In addition, lysis of the vaccine strain in the gut will reduce shedding[unreadable] of live vaccine strain to the environment. The novelty of our approach consists in manipulating a bacterial[unreadable] quorum sensing pathway to alter the course of an infective process and to achieve programmed antigen[unreadable] delivery and lysis of the vaccine vector in the host.